Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0239946 (liver fibrosis)
 8,268 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Liver fibrosis results from the excessive secretion of matrix proteins by hepatic stellate cells (HSC), which proliferate during fibrotic liver injury. We have studied a model of spontaneous recovery from liver fibrosis to determine the biological mechanisms mediating resolution. Livers were harvested from rats at 0, 3, 7, and 28 d of spontaneous recovery from liver fibrosis induced by 4 wk of twice weekly intraperitoneal injections with CCl4. Hydroxyproline analysis and histology of liver sections indicated that the advanced septal fibrosis observed at time 0 (peak fibrosis) was remodeled over 28 d of recovery to levels close to control (untreated liver). alpha-Smooth muscle actin staining of liver sections demonstrated a 12-fold reduction in the number of activated HSC over the same time period with evidence of HSC apoptosis. Ribonuclease protection analysis of liver RNA extracted at each recovery time point demonstrated a rapid decrease in expression of the collagenase inhibitors TIMP-1 and TIMP-2, whereas collagenase mRNA expression remained at levels comparable to peak fibrosis. Collagenase activity in liver homogenates increased through recovery. We suggest that apoptosis of activated HSC may vitally contribute to resolution of fibrosis by acting as a mechanism for removing the cell population responsible for both producing fibrotic neomatrix and protecting this matrix from degradation via their production of TIMPs.
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PMID:Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. 969 Oct 91

Hepatic stellate cells play a central role in the pathogenesis of liver fibrosis, both via production of extracellular matrix proteins and through secretion of matrix metalloproteinases. In this study, effects of soluble cell adhesion peptides on collagen type I accumulation and on expression of matrix metalloproteinases were analyzed. First, we revealed the expression of alpha5-integrin on hepatic stellate cells by immunostaining. Treatment with 100 microg/ml of soluble Arg-Gly-Asp (RGD) peptides was found to reduce accumulation of type I collagen without any effects on its transcriptional level in rat hepatic stellate cells, whereas a control peptide Gly-Arg-Gly-Glu-Ser (GRGES) had no such effect. Soluble RGD peptides also increased the secretion of collagenase by stellate cells. These data suggested that reduced accumulation of type I collagen caused by the RGD peptide ligation to integrins on hepatic stellate cells was partly due to stimulated expression of collagenase by stellate cells.
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PMID:Soluble Arg-Gly-Asp peptides reduce collagen accumulation in cultured rat hepatic stellate cells. 1023 16

In liver fibrosis, activated hepatic stellate cells (HSC) play a major role in the deposition of excess extracellular matrix, including fibrillar collagens type I and type III. In addition to matrix protein synthesis, HSC regulate matrix degradation in the liver. This is mediated via a combination of synthesis of matrix (pro)metalloproteinases, which activate these zymogens via specific mechanisms and by inhibiting the active matrix-degrading enzymes via expression of tissue inhibitors of metalloproteinases (TIMPs). There are currently four members of the TIMP family described and of these, both TIMP-1 and TIMP-2 are synthesised by HSC. These observations have led to the suggestion that inhibition of matrix degradation mediated by a change in HSC-expression of TIMPs relative to metalloproteinases, such as interstitial collagenase, may contribute to progression of liver fibrosis. This hypothesis is supported by studies of human liver disease in which TIMP-1 expression is upregulated 5-fold in cirrhotic compared with normal liver. TIMP-1 and TIMP-2 expression is also upregulated in animal models of progressive fibrosis, whereas expression of collagenase is unchanged. In a model which is characterized by natural resolution of liver fibrosis, degradation of the deposited fibrillar liver matrix is accompanied by rapid down-regulation of TIMP-1 expression. In alcoholic liver disease, the role of TIMPs has not been studied exhaustively, but the evidence currently available supports a role for inhibition of matrix degradation by TIMPs in this progressive fibrotic liver disease.
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PMID:Tissue inhibitors of metalloproteinases: role in liver fibrosis and alcoholic liver disease. 1037 19

The participation of matrix metalloproteinases (MMP) and their specific inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMP), in both the formation and degradative recovery processes of liver fibrosis were mainly reviewed from the molecular biological aspect. Since authors first reported increased activity of interstitial collagenase in the early stage of hepatic fibrosis in rats induced by chronic CCl4 intoxication, in baboons fed alcohol chronically and in patients with alcoholic fibrosis, other investigators have also demonstrated increased activity biologically and histochemically. However, species-specific differences in response have been found and gene-level research on the rat model has not demonstrated increased mRNA transcription of collagenase. It has also been clarified that activated stellate cells can also produce matrix components. Very recently, authors observed the participation of interstitial collagenase in the recovery from experimental hepatic fibrosis by using polymerase chain reaction northern blotting and in situ hybridization. The in situ hybridization findings not only demonstrated the cells responsible for interstitial collagenase, but also suggested a great deal about the mechanism of recovery from fibrosis. Hepatic stellate cells are activated via the expression of c-myb and nuclear factor-kappaB (NFkappaB) which is induced by oxidative stress, and inhibited by antioxidant (1-alpha-tocopherol) and butylated hydroxytoluene. The activation mechanism is now being revealed. The relationship between the activation mechanism of stellate cells and the production and secretion of MMP and TIMP in the formation and recovery process of hepatic fibrosis should be investigated from the promoter gene level. This approach might help develop a new strategy for the treatment of liver fibrosis.
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PMID:Molecular mechanism of the reversibility of hepatic fibrosis: with special reference to the role of matrix metalloproteinases. 1075 17

Decorin is a small extracellular matrix proteoglycan. It binds and modulates transforming growth factor (TGF)-beta 1 action, the major stimulator of fibrogenesis. Its role in the pathogenesis of human liver cirrhosis is unknown. Therefore, we studied the relationship of the 2 proteins in normal human liver and in 43 chronic hepatitis and liver cirrhosis specimens. To understand the mechanism that maintains matrix deposition in stage IV hepatitis, we studied expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, as well as the activities of type IV collagenases. Gene expression was analyzed on messenger RNA and protein level by morphologic and biochemical approaches. Decorin proved to be an early marker of fibrogenesis, and its deposition increased parallel to that of TGF-beta 1 and to inflammatory activity. Liver fibrosis progressed despite high temporospatial expression of decorin with TGF-beta 1. Neither decorin nor TGF-beta 1 protein deposition increased further in cirrhosis with low inflammatory activity, suggesting that impaired extracellular matrix catabolism rather than active production plays a role in this stage. This possibility was supported by high message levels of metalloproteinase inhibitors, no 72-kd collagenase activities, and low 92-kd collagenase activities.
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PMID:Expression of decorin, transforming growth factor-beta 1, tissue inhibitor metalloproteinase 1 and 2, and type IV collagenases in chronic hepatitis. 1134 37

Since the authors reported the presence of collagenase in the liver as well as its increased activity in the early stage of hepatic fibrosis and its reduced activity in advanced fibrosis in rats induced by chronic CCl4 intoxication, in baboons fed alcohol chronically and in patients with alcoholic fibrosis, other investigators have demonstrated the same tendency of collagenase activity biologically and histochemically. Very recently, the authors demonstrated definite gene expression of collagenase during the recovery from experimental hepatic fibrosis using Northern blotting and in situ hybridization. The findings of in situ hybridization not only demonstrated the cells expressing collagenase, but also suggested much information on the mechanism of the recovery from fibrosis. Hepatic stellate cells play a key role not only in fibrogenesis but also in fibrolysis. The authors' recent observation revealed that collagenase (matrix metalloproteinase-13 (MMP-13)) gene expression appears very early in the process of recovery from liver fibrosis, and that both stellate cells and hepatocytes express MMP-13. Recovery from liver cirrhosis requires the gene expression of collagenase, increased production of the collagenase enzyme, and activation of the enzyme balanced with the specific inhibitors of collagenase. The understanding of molecular mechanisms of MMP-1 gene expression which is under investigation in our laboratory may provide us a new strategy for the treatment of liver fibrosis including the possibility of gene therapy.
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PMID:Reversibility of hepatic fibrosis: from the first report of collagenase in the liver to the possibility of gene therapy for recovery. 1145 May 93

The activated hepatic stellate cell (HSC) is central to liver fibrosis as the major source of collagens I and III and the tissue inhibitors of metalloproteinase-1 (TIMP-1). During spontaneous recovery from liver fibrosis, there is a decrease of TIMP expression, an increase in collagenase activity, and increased apoptosis of HSC, highlighting a potential role for TIMP-1 in HSC survival. In this report, we use tissue culture and in vivo models to demonstrate that TIMP-1 directly inhibits HSC apoptosis. TIMP-1 demonstrated a consistent, significant, and dose-dependent antiapoptotic effect for HSC activated in tissue culture and stimulated to undergo apoptosis by serum deprivation, cycloheximide exposure, and nerve growth factor stimulation. A nonfunctional mutated TIMP-1 (T2G mutant) in which all other domains are conserved did not inhibit apoptosis, indicating that inhibition of apoptosis was mediated through MMP inhibition. Synthetic MMP inhibitors also inhibited HSC apoptosis. Studies of experimental liver cirrhosis demonstrated that persistent expression of TIMP-1 mRNA determined by PCR correlated with persistence of activated HSC quantified by alpha smooth muscle actin staining, while in fibrosis, loss of activated HSC correlated with a reduction in TIMP-1 mRNA. We conclude that TIMP-1 inhibits apoptosis of activated HSC via MMP inhibition.
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PMID:Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis. 1179 25

AIM:To study the mechanism of Fuzhenghuayu (FZHY) decoction on anti-liver fibrosis.METHODS:FZHY 10% decoction sera was incubated with rat normal subcultured hepatic stellate cells (HSC) and fibrotic primarily cultured HSC, normal and fibrotic hepatocytes and subcultured skin fibroblasts seperately. Cell intracellular and extracellular collagen synthesis rates were measured by the method of (3)H Proline impulse and collagenase digestion.RESULTS:For primarily cultured HSC and hepatocytes, both of intracellular and extracellular collagen synthesis rates decreased in the drug sera group. For the normal subcultured HSC and primarily cultured hepatocytes, the extracellular collagen secretion was decreased obviously by the drug sera, and intracellular collagen synthesis rates were inhibited to some extents.For fibroblasts, both intracellular and extracellular collagen synthesis rates were inhibited somewhat, but no significant differences were found.CONCLUSION:The mechanism of FZHY decoction on anti-liver fibrosis may be associated with inhibition of liver collagen production.
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PMID:Effects of Fuzhenghuayu decoction on collagen synthesis of cultured hepatic stellate cells, hepatocytes and fibroblasts in rats. 1181 68

AIM:To investigate the mechanisms of salvianolic acid A (SA-A) against liver fibrosis in vitro.METHODS:NIH/3T3 fibroblasts were cultured routinely, and incubated with 10(-4) mol/L-10(-7)mol/L SA-A for 22h. The cell viability was assayed by (3)H proline incorporation, cell proliferation by (3)H TdR incorporation, cell collagen synthetic rate was measured with (3)H proline impulse and collagenase digestion method.The total RNA was prepared from the control cells and the drug treated cells respectively, and alpha(1) I pro-collagen mRNA expression was semi-quantitatively analyzed with RT-PCR.RESULTS:10(-4)mol/L SA-A decreased cell viability and exerted some cytotoxiciy,while 10(-5)mol/L -10(-7)mol/L SA-A did not affect cell viability, but inhibited cell proliferation significantly, and 10(-6)mol/L SA-A had the best effect on cell viability among these concentrations of drugs. 10 (-5)mol/L -10(-6)mol/L SA-A inhibited intracellular collagen synthetic rate, but no significant influence on extracellular collagen secretion. Both 10(-5)mol/L and 10(-6)mol/L SA-A could decrease alpha(1)I pro-collagen mRNA expression remarkably.CONCLUSION:SA-A had potent action against liver fibrosis. It inhibited NIH/3T3 fibroblast proliferation, intracellular collagen synthetic rate and type I procollagen gene expression, which may be one of the main mechanisms of the drug.
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PMID:Effects of salvianolic acid-A on NIH/3T3 fibroblast proliferation, collagen synthesis and gene expression. 1181 98

Dietary nucleotides reportedly promote functionality and repair in fibrotic liver. Liver fibrosis is characterized by an excessive accumulation of extracellular matrix components, which lead to the impairment of the hepatic function. The aim of this work was to evaluate the influence of dietary nucleotides on liver fibrosis induced by thioacetamide and to elucidate the mechanism by which nucleotides exert their protective effects. Rats consumed ad libitum 300 mg/L thioacetamide in drinking water and were pair-fed diets with (group TN) or without nucleotides (group TS) for 4 mo. Liver histology and extracellular matrix components, liver collagenase and prolyl 4-hydroxylase activities, and tissue inhibitor of metalloproteinases-1 were assessed. The degree of fibrosis was lower in group TN than in group TS. Group TN had lower hepatic concentration of hydroxyproline (P < 0.05), collagen type I (P = 0.12) and type III (P = 0.20), fibronectin (P = 0.05), laminin (P = 0.11) and desmin (P = 0.07), higher collagenolytic activity (P < 0.05), lower prolyl 4-hydroxylase activity (P < 0.05) and lower prolyl 4-hydroxylase (P = 0.10) and tissue inhibitor of metalloproteinase-1 (P = 0.06) expression than group TS. Moreover, expression of tissue inhibitor of the metalloproteinases-1 gene was lower in group TN than in group TS (P < 0.05). These data indicate that the reduction of liver fibrosis in nucleotide-supplemented rats may rely on the enhancement of collagenase activity and the reduction of collagen content and maturation.
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PMID:Dietary nucleotide supplementation reduces thioacetamide-induced liver fibrosis in rats. 1192 56


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